Migranal Nasal Spray
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
MIGRANAL 4mg/ml nasal spray solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml nasal spray solution contains 4.0 mg dihydroergotamine mesilate.
Each metered dose delivers 0.5mg dihydroergotamine mesilate.
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Nasal spray, solution.
MIGRANAL Nasal Spray is a liquid dosage form for local application using a spray device. The liquid is a clear, colourless to faintly yellow, brownish-yellow or greenish-yellow solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of acute attacks of migraine with or without aura
4.2 Posology and method of administration
One spray (0.5 mg) of MIGRANAL Nasal Spray should be administered in each nostril at the onset of the migraine headache.
Fifteen minutes later, in patients in whom the first dose of MIGRANAL Nasal Spray (1.0 mg) was not sufficient, one additional spray (0.5 mg) can be administered in each nostril for a total dosage of four sprays (2.0 mg) of MIGRANAL Nasal Spray per attack.
The following recommendations must be observed:
The maximum dose of MIGRANAL Nasal Spray allowed within 24 hours is 2 mg (= 4 sprays) and the maximum weekly dose is 8mg (= 16 sprays).
Following the treatment of a migraine attack with MIGRANAL Nasal Spray, an interval of at least 24 hours should be observed before treating any further attack with
MIGRANAL Nasal Spray. Dihydergot injections, any ergotamine-containing preparations, sumatriptan or other agonists of the 5-hydroxytryptamine1 (5-HT1) receptors.
The assembled nasal spray should be discarded after the treatment of a single migraine attack as described above (1 mg or 2 mg, respectively).
Instructions for use
Only prepare the nasal spray when you feel an attack of migraine starting. Once the spray device is assembled, it should be used within 8 hours.
1. Pull back the blue seal by lifting up at the lip, but do not break the blue seal off the metal collar.
2. Tear off the whole cap and metal collar. The blue seal and metal collar should come off in one piece. If the blue seal snaps off, continue to remove the metal collar but take extra care as the edges of the metal collar may be sharp.
3. Carefully remove the rubber stopper from the bottle.
4. Gently remove the plastic protective cap from the bottom of the pump unit.
5. Insert the nasal spray pump unit into the open bottle and turn the pump clockwise to tighten.
6. Holding the bottle upright, gently remove the blue protective cap from the top of the nozzle.
7. The pump unit must be primed before first use. To do this hold the nasal spray upright and press down firmly on the pump 4 times. Do not worry if a small amount of medicine sprays out during the priming process, this is normal.
8. Holding the spray upright, insert the nozzle and spray once into each nostril. Sniff vigorously several times to prevent the solution from running out of your nose. Do not blow your nose immediately after taking a dose.
Replace the blue cap and keep the spray unit handy in case you need it again later.
You do not need to reprime the pump.
Elderly
MIGRANAL Nasal Spray is not recommended for use in patients aged over 65 years due to a lack of data on safety and efficacy.
Children
MIGRANAL Nasal Spray is not recommended for use in children aged below 16 years due to a lack of data on safety and efficacy.
4.3 Contraindications
Known hypersensitivity to ergot alkaloids or any other components of the formulation (see 6.1).
Conditions predisposing to vasospastic reactions: coronary heart disease (in particular unstable or vasospastic angina), septic conditions, shock, obliterative vascular disease; peripheral vascular diseases such as Raynaud's syndrome, past history of transitory ischemic attack or cerebral injury as well as inadequately controlled hypertension.
Temporal arteritis
Treatment of familial hemiplegic migraine.
Treatment of basilar migraine.
Pregnancy and breast-feeding (see section 4.6).
Patients with severely impaired hepatic function.
Concomitant treatment with potent CYP 3A inhibitors, such as macrolide antibiotics, HIV-protease inhibitors, azole antifungals and other medications (see section 4.5).
Concomitant treatment with peripheral vasoconstrictive agents including ergot containing preparations, sumatriptan and other agonists of the 5-hydroxytryptaminei (5-HTi) receptors. (see section 4.5).
4.4 Special warnings and precautions for use
MIGRANAL Nasal Spray is not intended for use as a prophylactic treatment for migraine.
Chronic daily use of MIGRANAL Nasal Spray or its use in excess of the recommended doses should be avoided, since it may cause vasospasm.
Chronic abuse of MIGRANAL Nasal Spray may cause rebound headache. If such condition is suspected, the treatment should be discontinued.
In rare cases, vascular spasms may occur, particularly in the lower extremities. If signs of vascular spasms are observed, MIGRANAL Nasal Spray should be discontinued and treatment with a peripheral vasodilator initiated (see section 4.9).
Patients who are being treated with MIGRANAL Nasal Spray should be informed of the maximal allowed doses and of the first symptoms of overdosage: paraesthesia (e.g. numbness, tingling) in the fingers and toes, non-migraine-related nausea and vomiting, and symptoms of myocardial ischaemia and chest pain.. Should signs of overdosage occur, treatment must be discontinued and patients should consult their physician at once. Patients a history of drug induced fibrotic disorders such as retroperitoneal and pleural fibrosis, should be monitored with caution.
Caution is recommended in patients with rhinitis, nasal congestion and allergic rhinitis as well as in patients with mild to moderate hepatic impairment, especially in patients with cholestatic hepatitis.
Note:
The solution contained in the amber-glass vials is specially formulated for intranasal administration and must not be injected.
4.5 Interaction with other medicinal products and other forms of interaction
The concomitant use of potent cytochrome P450 3A (CYP3A) inhibitors together with MIGRANAL Nasal Spray is contraindicated. Potent CYP3A inhibitors include macrolide antibiotics (e.g. erythromycin, clarithromycin, troleandomycin telithromycin,), HIV protease inhibitors (e.g. indinavir, nelfinavir, ritonavir), efavirenz, azole antifungals (e.g. ketoconazole, itraconazole, voriconazole), quinupristine-dalfopristine, delavirdine, or nefazodone. Concomitant administration can result in an elevated exposure to dihydroergotamine and ergot toxicity (vasospasm and ischaemia of the extremities and other tissues). (see section 4.3).
Concurrent use of vasoconstrictive agents including ergotamine-containing preparations, other ergot alkaloids, triptans (e.g. sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan and frovatriptan) is contraindicated since this may result in enhanced vasoconstriction. (see section 4.3).
In view of its vasoconstrictor properties caution is advised with concomitant use of nicotine (e.g. heavy smoking, nicotine replacement therapy)
MIGRANAL Nasal Spray should not be used within 6 hours after sumatriptan or other 5-HT1 agonists. Although the combination of ^-adrenergic blocking agents (e.g. propranolol) and MIGRANAL Nasal Spray is usually well tolerated, caution is required in patients with impaired peripheral circulation.
4.6 Pregnancy and lactation
MIGRANAL Nasal Spray is contraindicated during pregnancy.
Clinical practice with parenteral administration of dihydroergotamine suggests that because of uterotonic activity and vasoconstrictive effects on the placenta and umbilical cord, dihydroergotamine may he hazardous for the foetus.
Studies in animals have shown reproductive toxicity (see section 5.3)
It is likely that dihydroergotamine is excreted in breast milk. MIGRANAL Nasal Spray is therefore contraindicated for nursing mothers.
4.7 Effects on ability to drive and use machines
Patients who experience dizziness or other central nervous system disturbances, including visual disturbances, following use of MIGRANAL Nasal Spray should not drive or operate machinery.
4.8 Undesirable effects
The most frequently reported adverse reactions are rhinitis, nausea and vomiting, altered sense of taste, dose-dependent application-site reactions such as runny and stuffy nose, diarrhoea, pharyngitis, dizziness and flushing.
Frequencies are defined as: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (< 1/1,000), unknown (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
|
Immune system disorders Rare |
Hypersensitivity reactions (such as skin rash, face oedema, urticaria and dyspnoea) |
|
Nervous system disorders | |
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Uncommon |
Paraesthesia/hypoaesthesia, dizziness, |
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taste disturbance | |
|
Cardiac disorders | |
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Rare |
Symptoms of myocardial ischaemia |
|
Vascular disorders | |
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Uncommon |
Flushing |
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Rare |
Arterial spasm (particularly in the lower |
|
extremities) (see sections 4.4 and 4.9) | |
|
Respiratory, thoracic and mediastinal disorders | |
|
Uncommon |
Nasal congestion, rhinitis |
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Rare |
Pharyngitis |
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Unknown |
Epistaxis |
|
Skin and subcutaneous tissue disorders | |
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Rare |
Rash, face oedema, urticaria |
|
Musculoskeletal and connective tissue disorders | |
|
Unknown |
Muscular spasm |
|
Gastrointestinal disorders | |
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Uncommon |
Nausea, vomiting |
|
Rare |
Diarrhoea |
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Unknown |
Abdominal pain |
|
General disorders and administration site conditions | |
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Uncommon |
Application site reactions |
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Rare |
Chest pain |
4.9 Overdose
No case of overdosage with MIGRANAL Nasal Spray is known. One may, however, expect the symptoms to be similar to those observed after an excessive oral dose, i.e.: nausea, vomiting, headache, tachycardia, vertigo, peripheral signs and symptoms of vasospasm (e.g. numbness, tingling and pain in the extremities), symptoms of myocardial ischaemia, chest pain and coma. It should be noted that symptoms of vasospasm can be delayed up to 24 hours after drug administration.
After discontinuation of use, the treatment of overdose is symptomatic, under close monitoring of the cardiovascular system.
In the event of severe vasospastic reactions, intravenous administration of a peripheral vasodilator such as nitroprusside, phentolamine or dihydralazine, local application of warmth to the affected area and nursing care to prevent tissue damage are recommended. In the case of coronary constriction, appropriate treatment such as nitroglycerine should be initiated.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ergot alkaloids, ATC-code: N02CA01
Dihydroergotamine displays moderate to high affinity for various serotonin receptor subtypes. It displays particularly potent agonist activity at the 5-HT1D receptor which is believed to underlie its antimigraine efficacy. This agonistic effect produces a reduction in 5-HT neuronal function and thereby influences elements of the cranial vasculature and/or prevents neurogenic inflammation and the resultant stimulation of nociceptors.
The administration of MIGRANAL Nasal Spray provides a rapid onset of action. In acute migraine attacks of mild to severe intensity, MIGRANAL Nasal Spray reduces headache pain and associated symptoms such as phonophobia and/or photophobia.
5.2 Pharmacokinetic properties
Intranasally administered dihydroergotamine is rapidly absorbed (tmax approx. 45 min). The absolute bioavailability of dihydroergotamine via the intranasal route is about 43 ± 24 %. Between 70 and 80% of the plasma concentration is related to unchanged drug, pointing to a lower metabolism of parent drug than that obtained with oral administration.
Dihydroergotamine is 93% bound to plasma proteins. Its apparent steady-state volume of distribution is about 800 litres. Total body clearance is about 1.5 litres/minute, reflecting mainly hepatic clearance. Elimination from the plasma is biphasic, with a terminal half-life of about 10 hours. The major route of excretion is via the bile in the faeces. After intranasal administration, the urinary excretion of parent substance and metabolites amounts to about 2%.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on the nasal and oral studies of repeated dose toxicity, safety pharmacology, validating kinetics and metabolism studies. The only significant effect was a mild irritant effect on the nasal mucosa of laboratory animals. MIGRANAL Nasal Spray is considered to have a transient weak irritant potential. In one in vitro test in mammalian cells slight increases in frequency of chromosome aberrations were found. This single positive result is not considered to be of biological relevance, since 8 other in vitro and in vivo tests were negative. In a rat carcinogenicity study, there was no evidence of a carcinogenic effect.
Animal studies did not reveal any teratogenic activity and no harmful effects were found with respect to the course of gestation, parturition and postnatal development. Minor effects (reduced foetal weight and/or delayed ossification) were encountered at high dose levels in some studies.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Caffeine
Glucose, anhydrous Purified water
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
Once opened, the vial solution has an in-use shelf-life of 8 hours.
6.4 Special precautions for storage
Do not store above 25°C
6.5 Nature and contents of container
MIGRANAL Nasal Spray is available in packs containing 1 ml solution in a 3.5 ml vial made of hydrolytic type I amber glass and a spray device consisting of a pump unit with a blue nozzle cover and a dip tube cover. The vial is closed with a rubber stopper sealed by a plastic flip-tear cap affixed to an aluminium metal collar.
After properly priming the spray device, MIGRANAL Nasal Spray contains at least 4 metered doses each of 0.125 ml spray solution.
Spray devices/vials are provided in cartons of 1,2 and 6. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
Amdipharm UK Limited Capital House,
85 King William Street,
London EC4N 7BL,
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 20072/0216
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
26/01/2007
10 DATE OF REVISION OF THE TEXT
25/05/2016